Introduction

Antimetabolites are a class of chemotherapeutics that compete with biologic substrates and interfere with many biochemical reactions in the cell. Following the introduction of aminopterin, a 4-amino analog of folic acid, for the treatment of childhood acute lymphocytic leukemia (ALL) in 1948 (Farber et al.), a less toxic analog, methotrexate (MTX) subsequently replaced aminopterin in the clinic in 1956 (Li, Hertz and Spencer). One year later, 5-fluorouracil (5-FU) was synthesized as an analog of uracil by Duschinsky and Heidelberg et al. It was subsequently determined to demonstrate anticancer activity in human tumors. The development of 5-FU is an excellent example of rational drug design, based on the observation that uracil is salvaged more efficiently by tumor cells compared to normal cells (Rutman, Cantarow and Paschkis, 1954). Both MTX and 5-FU are used to treat many kinds of cancer including head and neck, breast, gastrointestinal and bladder cancers. MTX is also used for maintenance and central nervous system prophylaxis of acute lymphoblastic leukemia.

The development of other effective drugs and combinations of drugs with antimetabolites has markedly improved the therapy of certain malignancies. Cytosine arabinoside (AraC), thiopurines (6-thioguanine, 6-TG and 6-mercaptopurine, 6-MP) and 2-chlorodeoxyadenosine (2-CdA) are other important antimetabolites that have been found effective for the treatment of acute leukemia (Henderson, Hoelzer and Freeman, 1990).

In potentially curable tumors, drug resistance occurs rapidly if cure is not achieved, and is the reason for treatment failure.